Antibiotic resistance ABCF proteins reset the peptidyl transferase centre of the ribosome to counter translational arrest
Murina, Victoriia ; Kasari, Marje ; Hauryliuk, Vasili LU
and Atkinson, Gemma C.
LU
(2018)
In Nucleic Acids Research
46(7).
p.3753-3763
- Abstract
Several ATPases in the ATP-binding cassette F (ABCF) family confer resistance to macrolides, lincosamides and streptogramins (MLS) antibiotics. MLS are structurally distinct classes, but inhibit a common target: the peptidyl transferase (PTC) active site of the ribosome. Antibiotic resistance (ARE) ABCFs have recently been shown to operate through direct ribosomal protection, but the mechanistic details of this resistance mechanism are lacking. Using a reconstituted translational system, we dissect the molecular mechanism of Staphylococcus haemolyticus VgaALC and Enterococcus faecalis LsaA on the ribosome. We demonstrate that VgaALC is an NTPase that operates as a molecular machine strictly requiring NTP hydrolysis (not just NTP... (More)
Several ATPases in the ATP-binding cassette F (ABCF) family confer resistance to macrolides, lincosamides and streptogramins (MLS) antibiotics. MLS are structurally distinct classes, but inhibit a common target: the peptidyl transferase (PTC) active site of the ribosome. Antibiotic resistance (ARE) ABCFs have recently been shown to operate through direct ribosomal protection, but the mechanistic details of this resistance mechanism are lacking. Using a reconstituted translational system, we dissect the molecular mechanism of Staphylococcus haemolyticus VgaALC and Enterococcus faecalis LsaA on the ribosome. We demonstrate that VgaALC is an NTPase that operates as a molecular machine strictly requiring NTP hydrolysis (not just NTP binding) for antibiotic protection. Moreover, when bound to the ribosome in the NTP-bound form, hydrolytically inactive EQ2 ABCF ARE mutants inhibit peptidyl transferase activity, suggesting a direct interaction between the ABCF ARE and the PTC. The likely structural candidate responsible for antibiotic displacement by wild type ABCF AREs, and PTC inhibition by the EQ2 mutant, is the extended inter-ABC domain linker region. Deletion of the linker region renders wild type VgaALC inactive in antibiotic protection and the EQ2 mutant inactive in PTC inhibition.
(Less)
- author
- Murina, Victoriia
; Kasari, Marje
; Hauryliuk, Vasili
LU
and Atkinson, Gemma C.
LU
- publishing date
- 2018-04-20
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Nucleic Acids Research
- volume
- 46
- issue
- 7
- pages
- 11 pages
- publisher
- Oxford University Press
- external identifiers
-
- scopus:85046975916
- pmid:29415157
- ISSN
- 1362-4962
- DOI
- 10.1093/nar/gky050
- language
- English
- LU publication?
- no
- additional info
- Copyright: This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine
- id
- 0b730552-09e4-4d5b-a6d8-c89fe60c4f3e
- date added to LUP
- 2021-09-24 20:38:25
- date last changed
- 2024-07-13 19:27:44
@article{0b730552-09e4-4d5b-a6d8-c89fe60c4f3e,
abstract = {{<p>Several ATPases in the ATP-binding cassette F (ABCF) family confer resistance to macrolides, lincosamides and streptogramins (MLS) antibiotics. MLS are structurally distinct classes, but inhibit a common target: the peptidyl transferase (PTC) active site of the ribosome. Antibiotic resistance (ARE) ABCFs have recently been shown to operate through direct ribosomal protection, but the mechanistic details of this resistance mechanism are lacking. Using a reconstituted translational system, we dissect the molecular mechanism of Staphylococcus haemolyticus VgaALC and Enterococcus faecalis LsaA on the ribosome. We demonstrate that VgaALC is an NTPase that operates as a molecular machine strictly requiring NTP hydrolysis (not just NTP binding) for antibiotic protection. Moreover, when bound to the ribosome in the NTP-bound form, hydrolytically inactive EQ2 ABCF ARE mutants inhibit peptidyl transferase activity, suggesting a direct interaction between the ABCF ARE and the PTC. The likely structural candidate responsible for antibiotic displacement by wild type ABCF AREs, and PTC inhibition by the EQ2 mutant, is the extended inter-ABC domain linker region. Deletion of the linker region renders wild type VgaALC inactive in antibiotic protection and the EQ2 mutant inactive in PTC inhibition.</p>}},
author = {{Murina, Victoriia and Kasari, Marje and Hauryliuk, Vasili and Atkinson, Gemma C.}},
issn = {{1362-4962}},
language = {{eng}},
month = {{04}},
number = {{7}},
pages = {{3753--3763}},
publisher = {{Oxford University Press}},
series = {{Nucleic Acids Research}},
title = {{Antibiotic resistance ABCF proteins reset the peptidyl transferase centre of the ribosome to counter translational arrest}},
url = {{http://dx.doi.org/10.1093/nar/gky050}},
doi = {{10.1093/nar/gky050}},
volume = {{46}},
year = {{2018}},
}